A Division of Medical Genetics consisting of coordinated diploid cell culture, biochemical laboratory and clinical counseling facilities is investigating three areas related to inherited disorders of amino acid metabolism. First, the feasibility of prenatal diagnosis through accurate genotyping of cultured cells is being investigated for maple syrup urine disease and through disciminant analysis of quantitative maternal plasma phenylalanine and tyrosine for phenylketonuria. Second, the genetic and biochemical control mechanisms of normal and mutant branched chain alpha-ketoacid dehydrogenase are being studied in normal and mutant cultured skin fibroblasts. High specific activity branched chain alpha-ketoacids labelled in the 1 position are synthesized and used as substrate for cell free enzyme systems and inner mitochondrial membrane matrix. Cofactor requirements, the effects of these cofactors on normal and mutant enzyme activity is correlated to in vivo response by patients with Maple Syrup Urine Disease. Third, the membrane transport phenomenon by which amino acids are bound, translocated and accumulated by cultured skin fibroblasts in monolayer is being defined in normal and "transport-mutant" lines derived from the skin of patients affected with glucose-galactose malabsorption and cystinuria. "Derepression" of mutant membrane function in these non-differentiated cell lines is being attempted by manipulation of media and transformation using chemical and viral techniques.